Sickle RBC are subject to a number of important cellular changes and selection pressures. In this study, we validated a biotin RBC label by comparison to the standard 51CR label, and used it to study changes that occur in sickle cells as they age. Sickle RBC had a much shorter lifespan than did normal RBC, but the two labels gave equivalent results for both cell types. A variable number of sickle, but not normal, RBC disappeared the circulation during the first few hours after reinfusion. The number of biotinylated sickle reticulocytes was decreased by fifty percent after 24 hours and 75% after 48 hours, with a gradual decrease in the amount of reticulum per cell. The labeled sickle cells exhibited major density increases during the first four to six days after reinfusion, with smaller changes thereafter. A small population of very light, labeled sickle RBC was essentially constant in number after the first few days. HbF content was determined in isolated biotinylated sickle RBC after reinfusion, allowing an estimate of lifespan for F cells and non-F cells. The lifespan of sickle B-RBC lacking HbF was estimated to be about two weeks, whereas F cells survived six to eight weeks.